There is a continuing need for effective alcohol metabolism inhibitors. This is so because some common alcohols, when ingested, are toxic. For example, methanol (wood alcohol), isopropyl alcohol (rubbing alcohol), and ethylene glycol (anti-freeze), are all toxic. When these compounds are ingested and metabolized in the liver, by liver alcohol dehydrogenases, the metabolic process first forms corresponding carbonyl compounds such as aldehydes, followed by further metabolism. For example, methanol is metabolized in the liver first to formaldehyde, then to formic acid. The increased acid content of the blood results in a lowering of the pH, which can be lethal. Accordingly, there is a real and continuing need for the development of alcohol metabolism inhibitors.
The function of the inhibitor is to prevent the ingested alcohol from being metabolized by alcohol dehydrogenases in the liver. If the ingested alcohol is prevented from being metabolized, eventually the alcohol will be excreted through the breath and the urine over a two to three day period. Since the harmful metabolic products are not formed, there is no significant toxicity to the organism.
The currently known treatments for ingestion of toxic alcohols include saturation of the organism with ethanol, the theory being that ethanol is a competitive inhibitor, and will be preferentially metabolized by the alcohol dehydrogenases in the liver, resulting in less metabolism of the ingested, toxic alcohol. The disadvantages of the use of ethyl alcohol for such treatments are, of course, that it is a depressant, that it is not a very effective inhibitor, and that it is only a competitive inhibitor.
There is therefore, a real and continuing need for inhibitors known as uncompetitive or noncompetitive inhibitors. These terms refer to an inhibitor compound whose effect cannot be reversed by the substrate (alcohol) during the metabolic oxidation process. There are, for example, certain amide compounds which are known to be uncompetitive inhibitors, see Sharkawi, M., Toxicology Letters, 1979, 4, 493-497. In addition, some slight inhibitory effect has been reported with dimethyl sulfoxide in the same article. However, surprisingly, the compounds of this invention are uncompetitive inhibitors which are as much as one thousandfold more effective than dimethyl sulfoxide. Such a dramatic increase in uncompetitive inhibition properties would not be predicted from the properties of dimethylsulfoxide.
Accordingly, it is the primary objective of the present invention is to develop truly useful uncompetitive or non-competitive inhibitors of the metabolism of alcohols.
It is another objective of the present invention to develop significant and effective alcohol metabolism inhibitors from tetramethylene sulfoxide and its three position substituted derivatives.
Another primary objective of the present invention is to develop certain novel substituted tetramethylene sulfoxide derivatives which, because of their potency and uncompetitive nature, are especially effective in inhibiting alcohol metabolism in animals.
Yet another objective of the present invention is to develop potent and uncompetitive alcohol metabolism inhibitors which are useful for the treatment of poisoning by methanol and ethylene glycol.
A further objective of the present invention is to prepare pharmaceutical compositions containing tetramethylene sulfoxide, or substituted tetramethylene sulfoxides, for use as inhibitors of the metabolism of alcohols.